Biomedical subjects
Publications and source records attributed to S A Blumenthal.
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Phosphorylase a activity was measured in hepatocytes from fed rats, some of which received ip chlorpropamide injections for 5 days preceding death (20 mg/100 g BW X day for 5 days). Chlorpropamide treatment significantly depressed basal phosphorylase a activity and lessened the increments in the activity of this enzyme induced by 10(-10) -10(-8) M glucagon and arginine vasopressin. The reductions in phosphorylase a activity after treatment with chlorpropamide were more than sufficient to explain the accompanying decreases in hepatic glucose production. Since glucagon and arginine vasopressin stimulate alternate pathways of phosphorylase activation and since chlorpropamide antagonizes both hormones, it is likely that the drug acts at or distal to the intracellular site (phosphorylase kinase) at which the two activation pathways converge.
Hepatocytes obtained from starved rats were incubated in oxygenated Krebs bicarbonate buffer containing 2% defatted bovine serum albumin. DL-alpha-Lipoic (dithio-octanoic) acid (1.0 mM) caused striking reductions in hepatic glucose output in the presence of each of the following substrates: pyruvate, lactate, alanine, dihydroxyacetone, glycerol, and fructose. With lactate as substrate, 0.1-1.0 mM-lipoate caused a concentration-dependent inhibition of gluconeogenesis. With the same substrate, e.g. lactate, 0.25-2.0 mM-octanoate abolished the effect of lipoate in a dose-dependent manner. Additional experimental data are presented which support the concept that the antigluconeogenic effects of lipoic acid in liver can be attributed largely, if not entirely, to sequestration of intramitochondrial coenzyme. A, presumably as lipoyl-CoA, bisnorlipoyl-CoA, or tetranorlipoyl-CoA.
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When hepatocytes isolated from fasted rats were incubated in medium containing 5 mmol/L pyruvate, addition of albumin-bound palmitate (0.5 mmol/L) increased fatty acid oxidation and the conversion of pyruvate to glucose. Similar stimulation of gluconeogenesis occurred when palmitate was added to hepatocytes in medium containing 5 mmol/L alanine. Addition of 0.5 mmol/L (+)-octanoylcarnitine, an inhibitor of fatty acid oxidation, prevented the increment in beta-oxidation, but not the increase in glucose formation from pyruvate or alanine, induced by palmitate. These studies and other data to be considered subsequently indicate that palmitate can stimulate hepatic gluconeogenesis from three-carbon precursors under conditions that preclude an increase in the formation of reducing equivalents by beta-oxidation.
Seven long-standing diabetic patients with spontaneous and intermittent hyperkalemia were studied in an effort to assess the normality of their renin-aldosterone axis. The administration of oral glucose, in the absence of insulin, caused a paradoxical rise in serum potassium with no significant change in plasma aldosterone concentration from controls. All displayed subnormal aldosterone-secreting capacity to known stimuli of aldosterone secretion such as low salt diet, angiotensin II infusion, and ACTH infusion. The paradoxical rise in serum potassium with hyperglycemia was corrected in all by concomitant administration of insulin or pretreatment with a mineralocorticoid. Our observations question the role of aldosterone deficiency in the phenomenon of glucose-induced hyperkalemia.
Consumption of nutrients and food energy was compared, with concomitant chemical and radiologic measurements of hepatic fat content, preoperatively and postoperatively in 25 patients who underwent gastric or jejunoileal bypass for obesity. Patients in the two operative groups ingested similar quantities of food before surgery. After surgery, caloric intake from all sources decreased in both groups but to a significantly greater extent in the gastric bypass patients. During the first six months postoperatively, the 13 gastric bypass patients showed no changes in hepatic fat content, whereas substantial increases in liver fat uniformly occurred in the 12 patients who had jejunoileal bypasses. It is suggested that dietary carbohydrate may have contributed to the accretion of liver fat in these 12 patients.
In perfused livers of rats fasted for 24 h, glucagon (5 x 10(-10) M) significantly elevated tissue and perfusate levels of cyclic AMP and caused a twofold increase in glucose formation from lactate. Chlorpropamide (0.8 x 10(-3) M) consistently blocked these effects. Measurements of metabolic intermediates suggest that chlorpropamide may inhibit gluconeogenesis by antagonizing the action of glucagon on the phosphoenolpyruvate cycle. In the experiments described, chlorpropamide did not lower hepatic ATP concentration or energy charge, and exerted its effects at perfusate concentrations comparable to serum concentrations reported in patients on maintenance doses of the drug.
In perfused livers of fed rats, chlorpropamide inhibits glucagon-stimulated glucose production by augmenting the action of insulin. This effect is associated with a decrease in cyclic AMP accumulation in liver and perfusate. Alterations in glucose production appear to correlate more closely with changes in the amount of cyclic AMP in the perfusate than with changes in intrahepatic concentration of nucleotide. Potenitation by chlorpropamide of the hepatic action of insulin does not require administration of the drug prior to perfusion. Further, it is demonstrable at concentrations of insulin and glucagon (10(-11M) that approximate the normal plasma levels of these hormones.
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Streptozotocin (STZ)-diabetic rats regularly retained sodium (Na+), and tended to retain potassium (K+) as well, in response to insulin. Diabetic patients have also been reported to exhibit antinatriuresis and antikaliuresis early in the course of insulin therapy. Insulin-related Na+ retention can occur without a marked reduction in blood glucose level and does not appear to be attributable to preexisting Na+ depletion, mineralocorticoid effect, or suppression of glucosuria. The decrease in urinary Na+ excretion (UNaV) in the rats incident to insulin administration was appreciably greater than the decrease in chloride (Cl-) or water excretion. The significance of this observation is uncertain. It may be, in part, a consequence of the nephrotoxicity of STZ. Insulin-related Na+ retention may be closely related pathogenetically to the Na+ retention of refeeding and may reflect a direct renal action of insulin or, less likely, an alteration of renal tubular metabolism in response to insulin-mediated changes in sytemic metabolism.
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